ADAM T Sepsis

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RE S EAR C H Open Access

The prognostic value of ADAMTS13 (a disintegrinand metalloprotease with thrombospondin type 1repeats, member 13) deficiency in septic shock patients involves interleukin-6 and is notdependent on disseminated intravascularcoagulationVincent Peigne

1,2

, Elie Azoulay2,5*

, Isaline Coquet2

, Eric Mariotte1,2

, Michael Darmon2

, Paulette Legendre1

,Nadir Adoui3, Anne Marfaing-Koka1,4 , Martine Wolf 1,4 , Benoit Schlemmer2 and Agns Veyradier1,4

Abstract

Introduction: ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13)deficiency has been reported in patients with sepsis but its clinical relevance and pathophysiology remain unclear.Our objectives were to assess the clinical significance, prognostic value and pathophysiology of ADAMTS13deficiency in patients with septic shock with and without disseminated intravascular coagulation (DIC).Methods: This was a prospective monocenter cohort study of patients with septic shock. Von Willebrand Factor,ADAMTS13-related parameters and plasma IL-6 concentration were measured at inclusion to the study. Patientswere categorized into three groups according to the presence of ADAMT13 deficiency (


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IntroductionSepsis is most frequently associated with hemostasis ab-normalities [ 1-3], especially disseminated intra-vascularcoagulation (DIC). DIC is characterized by the associ-ation of systemic activation of coagulation, impairmentof anticoagulant pathways and inhibition of fibrinolysis[4,5]. Manifestations of DIC, which is associated withan increased mortality during sepsis, include bleedingand microthrombi leading to organ failure [ 6]. Animalstudies and clinical trials reported that impairment of several anticoagulant pathways, like Protein C [ 7,8], tis-sue factor pathway inhibitor [ 9] or anti-thrombin [ 8],could also occur during sepsis. Substitution therapy with these factors has not been shown to improve sep-sis outcome [ 10,11].

Beside coagulation disturbances, abnormalities of vonWillebrand factor (VWF), related to endothelial damage,

have been reported in sepsis patients during the last dec-ade [12,13]. VWF is a multimeric glycoprotein crucialfor platelet adhesion and aggregation at the high shearrates of blood flow present in the microcirculation. Thelargest VWF multimers are the most adhesive to plate-lets and thus, the most efficient for primary hemostasis.Ultra-large VWF multimers (ULVWF) are physiologically present in endothelial cells and platelets, but absent inplasma. A metalloprotease, ADAMTS13 (a disintegrin andmetalloprotease with thrombospondin type 1 repeats,member 13), specifically cleaves ULVWF multimers andthus, regulates its adhesive function. A severe ADAMTS13

deficiency (activity


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thresholds defined by Angstwurm et al . [35] for scoring(that is, PI >70%: 0 points; 40 to 70%: 1 point; 12 U/mL, according to the manufacturer s in-structions). In both patients in whom the titer of anti-ADAMTS13 IgG was positive and/or whose ADAMTS13activity was below the median, an inhibitor assay was per-

formed as previously described [ 40]. Plasma IL-6 was de-termined using the Human IL-6 Quantikine ELISA kitfrom R&D Systems (Minneapolis, MN, USA).

Statistical analysisData are reported as numbers (percentages) or medians(IQR: 25th to 75th percentiles). Continuous variableswere compared using the Wilcoxon rank sum test andproportions using the Fisher exact test. Hospital mortal-ity was the outcome variable of interest. We performedunivariate logistic regression analysis to identify variablesthat significantly influenced the likelihood of mortality,as measured by the estimated odds ratio (OR) with the95% CI. All variables have been tested in univariate ana-lysis. Variables of interest were defined prior to study initiation. Logistic regression analysis was then per-formed to identify variables significantly associated withhospital mortality, as measured by the estimated ORwith the 95% CI. Variables yielding P -values lower than0.20 in the bivariate analyses were entered into backwardstepwise logistic regression models where hospital mor-tality was the variable of interest. The critical P -value forremoval was 0.1. Co-linearity and interactions weretested. The Hosmer-Lemeshow test was used to checkgoodness of fit. Given the number of events, a maximum

of three variables was allowed in the models. Overallsurvival was estimated using the Kaplan-Meier methodthen compared using the log-rank test. Analyses weredone using the Statview software package (SAS Institute,Carry, NC, USA).

ResultsBaseline characteristics and clinical courseOut of 72 enrolled patients, 46 (64%) were men. Median(IQR) age was 59 (50 to 71) years. Bacterial infectionwas documented in 44 (61%) patients. SAPS II and LODscores at admission were 56 (45 to 71) and 7 (5 to 10),respectively. Among the 72 patients, 46 had microbio-logical documentation of their septic shock, including,22 with pneumonia, 11 with pyelonephritis, 7 with colitisand 6 with catheter-related infections. Pathogens involvedwere Escherichia coli (n = 12), Streptococcus pneumoniae(n= 11), Pseudomonas aeruginosa (n = 7), Streptococcusspecies (n = 5), Staphylococcus aureus (n = 4) and miscel-laneous (n =7), namely, Salmonella typhi (n=2), Neisseriameningitides (n = 2), Klebsiella pneumonia (n = 2) and Acinetobacter baumannii (n = 1).

The ISTH score was >5 in 19 (26%) patients whotherefore had overt DIC. Among detectable values (in 68patients out of 72), median ADAMTS13 activity was30% (IQR 19 to 45, range 10 to 78) whereas ADAMTS13activity was undetectable (


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Impact of the coupled ADAMTS13 activity/DIC onprognosisTo respond to our primary objective focused on boththe interaction between DIC and ADAMTS13 and prog-nosis, we decided to divide the cohort into three groups.

As shown in Table 2, among the 72 patients with septicshock, 28 (39%) patients had no DIC and an ADAMTSactivity above the median (group 1); 33 (46%) patientshad either DIC (n = 8) or an ADAMTS13 activity below the median (n = 25) (group 2), and 11 (15%) patients hadboth DIC and an ADAMTS13 activity below the median(group 3). Four patients had ADAMTS13 activity


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IL-6 concentration was significantly different between thethree groups (group 1, 78 pg/mL; group 2, 318 pg/mL;group 3, 1835 pg/ml, P = 0.004) (Table 2) and clearly in-creased from group 1 to 3. Interestingly, IL-6 level wasconsiderably higher in patients whose ADAMTS13 ac-tivity was 30% (median 895 (IQR 330 to 1843) pg/mL and83 (IQR 43 to 118), P = 0.0003) (Table 1).

DiscussionSepsis-induced organ failure is associated with a micro-circulation damage process involving mainly platelet/fibrin-thrombi supporting DIC. In some cases, the po-tential addition of platelet/VWF thrombi due to an ac-quired ADAMTS13 functional deficiency and leading toso-called TMA-like lesions is highly suspected in clinicalarguments [ 41-43] but still remains debated in terms of prognosis and pathophysiology. Furthermore, in moststudies published so far, the subtle combination of DICand TMA-like lesions has been difficult to establish be-cause of the great heterogeneity of the sepsis cohortstested, involving mixed cases within the categories of

systemic inflammation, sepsis, septic shock, and sepsis-related multiple organ failure [ 20-26], some of themcomplicated by DIC and others not. In the currentstudy, we focused on a cohort of 72 patients with septicshock prospectively enrolled from a single ICU in orderto respond to two objectives: first, to analyze the inter-action between DIC and ADAMTS13 and its impact onprognosis, and second, to elucidate the pathophysio-logical mechanisms for ADAMTS13 deficiency. Thestrength of our study is to propose an approach basedon clinical practice supported by three groups to evalu-ate the prognostic value of ADAMTS13 in sepsis: weshowed that septic shock outcome is associated with afunctional deficiency of ADAMTS13 together with anincrease of IL-6, independently of DIC.

In our cohort, the median of ADAMTS13 activity was30%, which is in agreement with the literature [ 20-26] andmost patients (57/72= 79%) exhibited partial ADAMTS13functional deficiency (values


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which was further confirmed by the absence of correlationbetween the ISTH score and ADAMTS13 activity and by the lack of a significant difference in ADAMTS13 betweenDIC-positive and DIC-negative patients and in the ISTHscore between patients with ADAMTS13 activity >30%and


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TTP patients is very likely multifactorial and may alsohave an important impact on prognosis.

The association between functional partial deficiency of ADAMTS13 and clinical prognosis factors in sepsis raisesthe question of the relevance of this metalloprotease as apassive marker or, in contrast, as an actor in the patho-physiology of organ failure. First, normal ADAMTS13:Aglevels found in our cohort suggested that ADAMTS13functional deficiency was mainly related to a qualitativedefect and not to a quantitative defect secondary to asynthesis/secretion deficiency or to a degradation process

mediated by sepsis-related enzymes [ 20,44-48]. Second,direct catalytic inhibition of ADAMTS13 by IL-6, a cyto-kine highly secreted in sepsis, has been reported in vitrousing ULVWF strings secreted from human umbilical veinendothelial cells under flowing conditions [ 49]. Clinicalstudies focused on septic patients are controversial, show-ing either no correlation between ADAMTS13 activity and IL-6 levels [23] or in contrast, a strong inverse correl-ation between these parameters [ 21,24]. Interestingly,in the current study, we also found a strong inversecorrelation between ADAMTS13 activity and IL-6levels. Although this inverse correlation does not allow ex-trapolation of any causal relationship, this result suggestsa potential role of IL-6 in the functional deficiency of ADAMTS13 observed in septic shock. Additional studiesare needed to confirm these findings and to more clearly assess the role of IL-6 on ADAMTS13 activity. Also, inour study, the link between IL-6 levels and prognosisalready reported by other authors [ 50] may be mediatedby ADAMTS13 deficiency. In contrast, no relevant spe-cific autoantibodies to ADAMTS13 were detected,making unlikely the involvement of an autoimmuneprocess in sepsis-associated ADAMTS13 functional de-ficiency. Third, in all our patients, we found increasedVWF:Ag levels and the presence of UL-VWF multimers

in plasma. An overwhelming release of ULVWF multimersfrom activated endothelial cells may exhaust ADAMTS13activity by a consumption mechanism [ 44,46,49-54]. Inseptic patients, the literature is controversial either sup-porting this consumption process [ 20,21,24,25] or not[23]. Further studies are needed to confirm prognostic im-pact of ADAMTS13 deficiency and to validate a cutoff forADAMTS13 activity that may be used to assess outcomes,independently of other determinants of death.

Our study has several limitations. First, our study doesnot include any control group. Indeed, without this con-

trol group we do not know whether the current findingsare specific to septic shock and whether the observed re-lationship (or lack thereof) is similar to the relationshipin critically ill patients who do not have septic shock. Inaddition, the compared group had, as expected, differentseverity at study inclusion. However, the prognostic im-pact persisted after adjustment for patient severity, sug-gesting the prognostic association between ADAMTS13deficiency and outcome to be independent from initialseverity differences.

ConclusionOur study underlines that septic shock seems to be asso-ciated with partial functional deficiency of ADAMTS13,which mechanism is potentially related to IL-6-mediatedinhibition but is independent of DIC. As a consequence,

Table 4 Factors independently associated with hospitalmortality (conditional backward stepwise regressionmodel)

Odds ratio 95% CI P-value

SAPS II score, per point 1.11 1.01, 1.24


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excessively released ULVWF multimers are more slowly cleared from the circulation and generate spontaneousformation of microvascular platelet thrombi responsiblefor multivisceral organ failure. Last but not least, ourstudy emphasizes the role of ADAMTS13 as a prognosisfactor in septic shock. These data are in agreement withthe exciting concept of ADAMTS13 as a link betweeninflammation and thrombosis, which was recently devel-oped thanks to animal models [ 55-58]. In addition, thisstudy may bring new insights in the field of hemostasisinhibitor-based treatment in severe sepsis: indeed, althoughthe efficiency of coagulation inhibitors is still controversial[59], downregulation of VWF-mediated thrombosis by ex-ogenous ADAMTS13 brought by plasma infusions, or inthe future by plasma-purified or recombinant ADAMTS13,may be an interesting new approach targeted on primary hemostasis.

Key messages

Septic shock seems to be associated with partialfunctional deficiency of ADAMTS13, whichmechanism might be related to IL-6-mediatedinhibition.

ADAMTS13 is an independent prognostic factorduring septic shock.

No correlation was observed in this study betweenADAMTS13 deficiency and DIC.

ADAMTS13 deficiency may decrease clearance of

excessively released ULVWF multimers, leading tospontaneous microvascular platelet thrombiformation and multiple organ failure.

AbbreviationsADAMTS13: A disintegrin and metalloprotease with thrombospondin type 1repeats member 13; ADAMTS13:Ag: ADAMTS13 antigen; DIC: Disseminatedintravascular coagulation; ELISA: Enzyme-linked immunosorbent assay;Ig: Immunoglobulin; IL-6: Plasma interleukin (IL)-6; ISTH: International Societyfor Thrombosis and Haemostasis; LOD: Logistic Organ Dysfonction score;MV: Mechanical ventilation; OR: Odds ratio; PaO2 /FiO2: arterial partial pressureof oxygen/inspired oxygen fraction; PI: Prothrombin index; RRT: Renalreplacement therapy; SAPS II: Simplified Acute Physiology Score 2; TMA: Thrombotic microangiopathy; TTP: Thrombotic thrombocytopenicpurpura; ULVWF: Ultralarge von Willebrand Factor multimers; VWF: vonWillebrand Factor; VWF:Ag: von Willebrand Factor antigen.

Competing interests The authors declare that they have no competing interests.

Authors contributionsVP, EA, BS and AV conceived the study, participated in its design andcoordination and helped to draft the manuscript. IC, EM, NA and MDparticipated in study design, patient recruitment and performed thestatistical analysis. VP, PL, AMK, MW and AV carried out the biological testingand cytokine evaluation. All authors read and approved the final manuscript.

Acknowledgements The authors are grateful to S Thouzeau and S Savigny for expert technicalsupport. The primary funding source was the French Ministry of Health.Supported by a grant from the Assistance-Publique Hpitaux de Paris(AOM 00 06).

Author details1Inserm U770, Le Kremlin Bictre, Paris, France. 2Service de RanimationMdicale, Hpital Saint Louis, AP-HP, Paris et Facult de Mdecine Paris 7,Paris, France. 3Service de Biochimie, Hpital Saint Louis, AP-HP, Paris etFacult de Mdecine Paris 7, Paris, France. 4Service dHmatologiebiologique, Hpital Antoine Bclre, AP-HP, Clamart et Facult de Mdecine

Paris 11, Le Kremlin Bictre, France. 5

AP-HP, Hpital Saint-Louis, Medical ICU,Universit Paris-Diderot, Sorbonne Paris-Cit, Facult de Mdecine, 1 avenueClaude Vellefaux, 75010, Paris, France.

Received: 22 March 2013 Accepted: 28 October 2013Published: 18 November 2013

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doi:10.1186/cc13115Cite this article as: Peigne et al. : The prognostic value of ADAMTS13(a disintegrin and metalloprotease with thrombospondin type 1repeats, member 13) deficiency in septic shock patients involvesinterleukin-6 and is not dependent on disseminated intravascularcoagulation. Critical Care 2013 17:R273.

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